This invention relates to methods of producing .alpha..sub.2 -adrenergic receptor agonist activity. More particularly, this invention relates to the production of .alpha..sub.2 -adrenergic receptor agonist activity by contacting an .alpha..sub.2 -adrenergic receptor with an optionally substituted aminomethyl-4,5-dihydroxy (or alkoxy) indane or a pharmaceutically acceptable salt thereof.
The adrenergic nervous system plays a primary role in the neurogenic regulation of the cardiovascular system. The sympathetic outflow to the heart and peripheral vessels originates from the vasomotor center and travels along descending neuronal pathways interrupted by synapses, the switching units which transmit the neurological signal from higher to lower neurons and from nerve endings to cells of the effector organ. Transmission of the neurological signal across synapses is mediated chemically by a neurotransmitter which is stored in the vesicles of nerve endings. Upon arrival of the neurological signal, regulated quantities of neurotransmitter are released into the synapse where it combines with receptor sites in the cellular membrane of the next neuron or effector ogan, and excites the receptor cell to propagate the neurological signal or to produce an effect in an effector organ.
The principal natural neurotransmitters specific to the adrenergic nervous system are norepinephrine and epinephrine (hereinafter collectively referred to as "norepinephrine"), which mediate neurological transmission in some central noradrenergic neurons in the vasomotor center and elsewhere in the brain as well as peripherally in so-called postganglionic symphathetic neurons. Adrenergic receptors for norepinephine have been recognized to be proteins bound to membranes of effector cells. These receptors control the function of the effector cell, and through it the function of a whole organ or organ systems. Adrenergic receptors are highly specific for norepinephrine and can discriminate between it and may other transmitters and molecules. However, their discrimination capability is not complete, and other related catecholamines as well as various synthetic agents have been found to bind to adrenergic receptors.
Through observed responses of various tissues and organs to norepinephrine and related catecholamine-like compounds, it has been found that the nature of adrenergic receptors differs substantially in different tissues where they mediate different functions. In addition, adrenergic receptors from various tissues have been found to differ in their discriminatory abilities for other compounds. Based on the foregoing and other observations, adrenergic receptors have been classified into at least two major groups, i.e., the .alpha.-adrenergic receptors and the .beta.-adrenergic receptors. In addition, the .alpha.-groups of receptors have been further divided into the .alpha..sub.1 -adrenergic receptor sub-group and the .alpha..sub.2 -adrenergic receptor sub-group. The .alpha..sub.1 -adrenergic receptors have been characterized as being exitatory in nature, primarily functioning to result in peripheral vascular contraction. On the other hand, presynaptic .alpha..sub.2 -adrenergic receptors have been characterized as being inhibitory in nature, primarily functioning to inhibit transmitter release through inhibition of adenylate cyclase activity, while post-synaptic .alpha..sub.2 -adrenergic receptors may function to result in peripheral vascular contraction.
Inasmuch as the different groups and sub-groups of adrenergic receptors mediate different functions in different bodily tissues and organs, it is highly desirable to obtain chemical compounds or entities which are highly selective for limited types of receptor sites. In this manner, isolated symptoms can be effectively treated, without affecting other unrelated tissues and organs, by selectively agonizing or antagonizing a particular sub-group of receptor sites.
One compound which has been found to exhibit relatively specific binding affinity for .alpha..sub.2 -receptor sites is known as clonidine. The structure of clonidine is as follows: ##STR2## Clonidine has been shown to agonize .alpha..sub.2 -adrenergic activity and has been used as an antihypertensive agent to regulate .alpha..sub.2 -mediated functions. Although clonidine has been found to be useful as an .alpha..sub.2 -adrenergic receptor agonist, the search continues for new compounds having improved properties.